Lymphoma Tumor Biology

Lymphoma Tumor Biology

doc. MUDr. Ondřej Havránek, Ph.D.

doc. MUDr. Ondřej Havránek, Ph.D. — Project head

1st Faculty of Medicine of the Charles University

About us

Non-Hodgkin lymphomas are a heterogenous group of hematologic malignancies derived in more than 90% from B-lymphocytes, one subtype of white blood cells. B-cells are part of adaptive immune system and one of their main functions is to recognize antigens and differentiate into plasmatic cells to produce antibodies. Hallmark molecule of B-cells is B-cell receptor (BCR), which is specifically responsible for antigen binding and recognition. Majority of B-cell derived malignancies retain surface expression of BCR, which is actively signaling and supports growth and survival of tumor cells.

Similarly, as is heterogonous group of lymphomas, differences exist also in types of signaling it provides. In some lymphomas, BCR signals through “chronic active” type of BCR signaling that resembles normal signaling after antigen binding, in other lymphomas, BCR signaling resembles “tonic” type of signaling that normally provides basic signal necessary for survival of mature B-cells. However, many details and differences in BCR signal initiation and its transmission to individual signal mediators are not fully characterized. Inhibition of BCR signaling and its related signal mediators is also one of novel strategies of lymphoma treatment, but more information is needed to identify novel therapeutic targets or personalize use of existing inhibitors.

Latest developments in technology and related research resulted in unprecedented advancement in our understanding of mechanisms leading to lymphomagenesis, however, many mechanisms of aberrant signaling, metabolic changes, transcription regulation, or interactions of tumor cells with tumor microenvironment are still not clear.

Using advanced methods for targeted genomic modifications, protein-protein interactions detection, high-resolution microscopy, or intracellular biosensors, the general aim of our group is to address missing information about cellular processes critical for lymphoma development and tumor cell growth with contribution to basic knowledge of these processes in general.

 Specific Projects:

  • Describe differences and mechanisms of B-cell receptor signal initiation, its localization and interaction with signal mediators, and mechanisms of PI3K/AKT pathway activation in different types lymphomas and states of BCR signaling.
  • Identify biomarkers to personalize use of BCR signaling inhibitors.
  • Investigate novel candidates for gene expression dysregulation in lymphoma.
  • Investigate relationship of driver lymphoma characteristics on development of tumor microenvironment using lymphoma mouse models.

Further information can be found also at https://havranek-lab.lf1.cuni.cz/about-us

News

Publications

2025

Tkachenko A, Havranek O. Cell death signaling in human erythron: erythrocytes lose the complexity of cell death machinery upon maturation. Apoptosis. 2025 Feb 9. doi: 10.1007/s10495-025-02081-5. Epub ahead of print. PMID: 39924584. (IF 6.1)

Daumova L, Manakov D, Petrak J, Sovilj D, Behounek M, Andera L, Vit O, Souckova O, Havranek O, Dolnikova A, Renesova N, Tuskova L, Winkowska L, Bettazova N, Kupcova K, Kalbacova MH, Sikorova M, Trneny M, Klener P. Long-term adaptation of lymphoma cell lines to hypoxia is mediated by diverse molecular mechanisms that are targetable with specific inhibitors. Cell Death Discov. 2025 Feb 18;11(1):65. doi: 10.1038/s41420-025-02341-y. (IF 6.1)

Kot Y, Prokopiuk V, Klochkov V, Tryfonyuk L, Maksimchuk P, Aslanov A, Kot K, Avrunin O, Demchenko L, Kurmangaliyeva S, Onishchenko A, Yefimova S, Havranek O, Tkachenko A. Mn3O4 Nanocrystal-Induced Eryptosis Features Ca2+ Overload, ROS and RNS Accumulation, Calpain Activation, Recruitment of Caspases, and Changes in the Lipid Order of Cell Membranes. Int. J. Mol. Sci. 2025, 26, 3284. https://doi.org/ 10.3390/ijms26073284. (IF 4.9)

Hamova I, Maco M, Tkachenko A, Kupcova K, Velasova A, Trneny M, Mocikova H, Havranek O. Circulating tumor DNA as a powerful tool in diagnostics and treatment outcome prediction - focus on large B-cell lymphomas and follicular lymphomas. Expert Rev Mol Diagn. 2025 May 22:1-21. doi: 10.1080/14737159.2025.2500659. (IF 3.9)

2024

Kupcova K, Senavova J, Jura F, Herman V, Rajmonova A, Pacheco-Blanco M, Chrbolkova T, Hamova I, Davis RE, Havranek O. Vertical targeting of the PI3K/AKT pathway at multiple points is synergistic and effective for non-Hodgkin lymphoma. Exp Hematol Oncol. 2024 Nov 1;13(1):108. doi: 10.1186/s40164-024-00568-6. (IF 9.4)

Bettazova N, Senavova J, Kupcova K, Sovilj D, Rajmonova A, Andera L, Svobodova K, Berkova A, Zemanova Z, Daumova L, Herman V, Dolníkova A, Davis RE, Trneny M, Klener P, Havranek O. Impact of PIK3CA gain and PTEN loss on mantle cell lymphoma biology and sensitivity to targeted therapies. Blood Adv. 2024 Oct 22;8(20):5279-5289. doi: 10.1182/bloodadvances.2024013205. (IF 7.4)

Eken JA, Koning MT, Kupcova K, Sepúlveda Yáñez JH, de Groen RAL, Quinten E, Janssen J, van Bergen CAM, Vermaat JSP, Cleven A, Navarrete MA, Ylstra B, de Jong D, Havranek O, Jumaa H, Veelken H. Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL. J Exp Med. 2024 May 6;221(5):e20230941. doi: 10.1084/jem.20230941. (IF 15.3)

Malarikova D, Jorda R, Kupcova K, Senavova J, Dolnikova A, Pokorna E, Kazantsev D, Nozickova K, Sovilj D, Bellanger C, Chiron D, Andera L, Krystof V, Strnad M, Helman K, Klanova M, Trneny M, Havranek O, Klener P. Cyclin dependent kinase 4/6 inhibitor palbociclib synergizes with BCL2 inhibitor venetoclax in experimental models of mantle cell lymphoma without RB1 deletion. Exp Hematol Oncol. 2024 Mar 25;13(1):34. doi: 10.1186/s40164-024-00499-2.(IF 11.4)

Zemankova P, Cerna M, Horackova K, Ernst C, Soukupova J, Borecka M, Blümcke B, Cerna L, Cerna M, Curtisova V, Dolezalova T, Duskova P, Dvorakova L, Foretova L, Havranek O, Hauke J, Hahnen E, Hodulova M, Hovhannisyan M, Hruskova L, Janatova M, Janikova M, Jelinkova S, Just P, Kosarova M, Koudova M, Krutilkova V, Machackova E, Matejkova K, Michalovska R, Misove A, Nehasil P, Nemcova B, Novotny J, Panczak A, Pesek P, Scheinost O, Springer D, Stastna B, Stranecky V, Subrt I, Tavandzis S, Tureckova E, Vesela K, Vlckova Z, Vocka M, Wappenschmidt B, Zima T, Kleibl Z, Kleiblova P. A deep intronic recurrent CHEK2 variant c.1009-118_1009-87delinsC affects pre-mRNA splicing and contributes to hereditary breast cancer predisposition. Breast. 2024 Mar 25;75:103721. doi: 10.1016/j.breast.2024.103721. (IF 3.9)

Tkachenko A. Apoptosis and eryptosis: similarities and differences. Apoptosis. 2024 Apr;29(3-4):482-502. doi: 10.1007/s10495-023-01915-4. (IF 6.1)

Tkachenko A, Havranek O. Erythronecroptosis: an overview of necroptosis or programmed necrosis in red blood cells. Molecular and cellular biochemistry, 479(12), 3273–3291. https://doi.org/10.1007/s11010-024-04948-8. (IF 3.5)

Tkachenko A. Hemocompatibility studies in nanotoxicology: Hemolysis or eryptosis? (A review). Toxicology in vitro : an international journal published in association with BIBRA, 98, 105814. https://doi.org/10.1016/j.tiv.2024.105814. (IF 3.2)

Zlatar L, Knopf J, Singh J, Wang H, Muñoz-Becerra M, Herrmann I, Chukwuanukwu RC, Eckstein M, Eichhorn P, Rieker RJ, Naschberger E, Burkovski A, Krenn V, Bilyy R, Butova T, Liskina I, Kalabukha I, Khmel O, Boettcher M, Schett G, Butov D, Tkachenko A, Herrmann M. Neutrophil extracellular traps characterize caseating granulomas. Cell Death Dis. 2024 Jul 31;15(7):548. doi: 10.1038/s41419-024-06892-3. [PubMed] (IF 8.1)

Tkachenko A, Kupcova K, Havranek O. B-Cell Receptor Signaling and Beyond: The Role of Igα (CD79a)/Igβ (CD79b) in Normal and Malignant B Cells. Int. J. Mol. Sci. 2024, 25, 10. (IF 5.6)

Soukupova J, Stastna B, Kanwal M, Hojny J, Zemankova P, Borecka M, Cerna L, Cerna M, Cerna M, Curtisova V, Dolezalova T, Duskova P, Foretova L, Havranek O, Horackova K, Hovhannisyan M, Hruskova L, Chvojka S, Janatova M, Janikova M, Jelinkova S, Just P, Kalousova M, Kleiblova P, Kosarova M, Koudova M, Kral J, Krausova M, Krutilkova V, Machackova E, Matejkova K, Michalovska R, Nehasil P, Nemcova B, Novotny J, Palek M, Pesek P, Safarikova M, Scheinost O, Springer D, Stolarova L, Stranecky V, Subrt I, Tavandzis S, Tureckova E, Vesela K, Vlckova Z, Vocka M, Zima T, Macurek L, Kleibl Z; CZECANCA consortium. A comprehensive study evaluating germline FANCG variants in predisposition to breast and ovarian cancer. Cancer Med. 2024 Aug;13(16):e70103. doi: 10.1002/cam4.70103. (IF 2.9)

Kot Y, Klochkov V, Prokopiuk V, Sedyh O, Tryfonyuk L, Grygorova G, Karpenko N, Tomchuk O, Kot K, Onishchenko A, Yefimova S, & Tkachenko A. (2024). GdVO4:Eu3+ and LaVO4:Eu3+ Nanoparticles Exacerbate Oxidative Stress in L929 Cells: Potential Implications for Cancer Therapy. International Journal of Molecular Sciences, 25(21), 11687. https://doi.org/10.3390/ijms252111687. (IF 4.9)

Seňavová J, Rajmonová A, Heřman V, Jura F, Veľasová A, Hamová I, Tkachenko A, Kupcová K, & Havránek O. (2024). Immune Checkpoints and Their Inhibition in T-Cell Lymphomas. Folia biologica, 70(3), 123–151. https://doi.org/10.14712/fb2024070030123. (IF 1.1)

Prokopiuk V, Onishchenko A, Pazura Y, Bespalova I, Kökbaş U, Tryfonyuk L, Mateychenko P, Kot K, Kurmangaliyeva S, Kot Y, Yefimova S, & Tkachenko A. (2024). Nanostructured zinc carbonate hydroxide microflakes: assessing the toxicity against erythrocytes and L929 cellsin vitro. Nanotechnology, 36(8), 10.1088/1361-6528/ad9aac. https://doi.org/10.1088/1361-6528/ad9aac. (IF 2.9)

2023

Tkachenko A, Onishchenko A, Myasoedov V, Yefimova S, Havranek O. Assessing regulated cell death modalities as an efficient tool for in vitro nanotoxicity screening: a review. Nanotoxicology. 2023 Apr 21:1-31. doi: 10.1080/17435390.2023.2203239. (IF 5.88)

Tkachenko A, Onishchenko A. Zincoptosis: does it exist? Apoptosis. 2023 Mar 24. doi: 10.1007/s10495-023-01836-2. (IF 5.56)

Kral J, Jelinkova S, Zemankova P, Vocka M, Borecka M, Cerna L, Cerna M, Dostalek L, Duskova P, Foretova L, Foretova L, et al: Germline multigene panel testing of patients with endometrial cancer. Oncol Lett 25: 216, 2023. (IF 3.11)

Tkachenko A, Onishchenko A & Prokopiuk V. Do Marine Polysaccharides Carrageenans Modulate Non-apoptotic Regulated Cell Deaths ? (a Review). Curr. Pharmacol. Rep. (2023). https://doi.org/10.1007/s40495-023-00339-7

Tkachenko A, Havranek O. Redox Status of Erythrocytes as an Important Factor in Eryptosis and Erythronecroptosis. Folia Biologica. 2023 (IF 0.6)

2022

Maco M, Kupcova K, Herman V, Ondeckova I, Kozak T, Mocikova H, Havranek O; Czech Hodgkin Lymphoma Study Group. Circulating tumor DNA in Hodgkin lymphoma. Ann Hematol. 2022 Sep 8. doi: 10.1007/s00277-022-04949-x. (IF 4.03)

Klanova M, Kazantsev D, Pokorna E, Zikmund T, Karolova J, Behounek M, Renesova N, Sovilj D, Kelemen CD, Helman K, Jaksa R, Havranek O, Andera L, Trneny M, Klener P. Anti-apoptotic MCL1 Protein Represents Critical Survival Molecule for Most Burkitt Lymphomas and BCL2-negative Diffuse Large B-cell Lymphomas. Mol Cancer Ther. 2022 Jan;21(1):89-99. doi: 10.1158/1535-7163.MCT-21-0511. (IF 6.0)

Herbrich S, Baran N, Cai T, et al. Overexpression of CD200 is a stem cell-specific mechanism of immune evasion in AML. Journal for ImmunoTherapy of Cancer 2021;9:e002968. doi:10.1136/jitc-2021-002968. (IF 12.49)

Henderson J, Havranek O, Ma MCJ, Herman V, Kupcova K, Chrbolkova T, Pacheco-Blanco M, Wang Z, Comer JM, Zal T, Davis RE. Detecting Förster resonance energy transfer in living cells by conventional and spectral flow cytometry. Cytometry A. 2022 Oct;101(10):818-834. doi: 10.1002/cyto.a.24472. (IF 4.355)

2021

Vockova P, Molinsky J, Klanova M, Karban J, Spacek M, Havranek O, Kupcova K, Kazantsev D, Trneny M, Klener P. CD31/PECAM-1 impacts engraftment, growth and spread of mantle cell lymphoma cells and positively correlates with extramedullary involvement. Leuk Lymphoma. 2020 Nov 25:1-8. doi: 10.1080/10428194.2020.1849678. (IF 2.969)

Soukupova J, Zemankova P, Nehasil P, Kleibl Z; CZECANCA consortium (Kleibl Z, Soukupová J, Janatová M, Zemánková P, Černá M, Jelínková S, Král J, Macháčková J, Foretová L, Anousková D, Tavandzis S, Krutílková V, Roszková B, Koudová M, Lhota F, Černá L, Vávrová J, Kleiblová P, Urbanová M, Vočka M, Novotný J, Havránek O, Hrušková L, Michalovská R, Vlčková Z, Schwetzová D, Černá M, Hejnalová M, Jedličková N, Šubrt I, Zavoral T, Kosařová M, Vacínová G, Janíková M, Kratochvílová R, Curtisová V, Scheinost O, Dušková P, Stránecký V, Nehasil P, Macůrek L). Re: ERCC3, a new ovarian cancer susceptibility gene? Eur J Cancer. 2021 Jun; 150:278-280 (IF 9.2)

Szydłowski M, Garbicz F, Jabłońska E, Górniak P, Komar D, Pyrzyńska B, Bojarczuk K, Prochorec-Sobieszek M, Szumera-Ciećkiewicz A, Rymkiewicz G, Cybulska M, Statkiewicz M, Gajewska M, Mikula M, Gołas A, Domagała J, Winiarska M, Graczyk-Jarzynka A, Białopiotrowicz E, Polak A, Barankiewicz J, Puła B, Pawlak M, Nowis D, Golab J, Tomirotti AM, Brzózka K, Pacheco-Blanco M, Kupcova K, Green MR, Havranek O, Chapuy B, Juszczyński P. Inhibition of PIM Kinases in DLBCL Targets MYC Transcriptional Program and Augments the Efficacy of Anti-CD20 Antibodies. Cancer Res. 2021 Dec 1;81(23):6029-6043. doi: 10.1158/0008-5472.CAN-21-1023. (IF 13.3)